The rostral ventromedial medulla (RVM) has a well-documented role in modulation of nociceptive transmission, and several independent lines of evidence support a major contribution of this brainstem region to opiate antinociception. One approach to the analysis of opiate action is at the level of single unit neurophysiology. Neurons of the RVM can be divided into three classes based on the relationship of cell discharge to the occurrence of nocifensive reflexes such as the tail flick (TF). Cells of one class, termed "off-cells," pause just prior to withdrawal reflexes induced by noxious stimulation, and there is good evidence that these neurons are the RVM output neurons that inhibit nociceptive transmission and contribute to opiate antinociception. Off-cells are activated by morphine in doses which are sufficient to produce antinociception. This off-cell excitation is probably due to suppression of the activity of an inhibitory interneuron, since the direct cellular effects of opiates are generally effects of opiates are generally inhibitory. One likely candidate for the substance released by this inhibitory interneuron is the ubiquitous inhibitory neurotransmitter GABA. GABA is found in cell bodies and terminals in the RVM, and may contribute to the nociceptive modulating functions of this region. The overall aim of the proposed research is to determine the significance of GABA in inhibitory control of activity of these putative nociceptive modulating neurons in the RVM, specifically its role in opiate antinociception. Three general approaches will be used. First, the effects of RVM microinjection of GABA agonists and antagonists on the TF reflex and on morphine-induced antinociception will be determined in lightly-anesthetized rats. Second, extracellular single unit recording and iontophoresis will be used to determine the role of GABA-ergic inputs to physiologically-characterized RVM neurons. Blockade of the TF-related pause or spontaneously-occurring periods of quiescence in the off-cell by GABA antagonists would favor a role for GABA in inhibitory control of off-cells. Reversal of opiate-induced activation of off-cells by GABA agonists would be consistent with the notion that opiates activate off-cells by reducing GABA-mediated inhibition. Finally, recordings from single off-cells before and after pressure ejection of GABA antagonists in doses sufficient to block the TF will reveal any changes in cell activity that are correlated with changes in nocifensive responses. These studies will further our knowledge of intrinsic brain mechanisms for controlling nociceptive transmission. In particular, they will expand our understanding of opioid analgesia and the physiological role of endogenous opioid peptides.